Neurotrophins represent an important family of polypeptide growth factors which influence the proliferation, differentiation, survival and death of neuronal and non-neuronal cells during vertebrate development They have been proposed as therapeutic agents for neurodegenerative disorders and nerve injury However, clinical applications have met with very disappointing results, in part due to difficulties of delivery and pharmacokinetics in the nervous system and unanticipated side effects We have found a way to use small molecule ligands of G protein-coupled receptors (GPCR) to activate Trk receptors in the absence of neurotrophin binding These small molecules keep neurons alive by stimulating the actions of trophic factor receptors Ligands for G protein-coupled receptors represent a novel way of stimulating neurotrophin receptor signaling, however, the mechanism of this process is unknown This grant will investigate the cell biological mechanisms that account for transactivation of neurotrophin receptors in neurons and define the contribution of receptor trafficking and transport to this process Defining the proteins that regulate neurotrophin receptor internalization, translocation and signaling is critical to our understanding of normal neuronal development and function as well as perturbations that occur in response to injury or disease. Our findings are directly relevant to the understanding and treatment of neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis.